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1.
Br J Haematol ; 204(5): 1593-1594, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38602310

RESUMEN

In this issue, a nationwide retrospective Japanese study finds that, in a second opinion setting, one-third of bone marrow aspirates from patients suspected of myelodysplastic syndromes are heavily haemodiluted. Moreover, in four-fifths of such cases, the failure to obtain the correct material for diagnosis went undetected by the referring institution. These data are intriguing, but given their special set-up, caution should be exerted in transposing them to other countries. Commentary on: Ogata et al. Prevalence of massively diluted bone marrow cell samples aspirated from patients with myelodysplastic syndromes (MDS) or suspected MDS: A retrospective analysis of nationwide samples in Japan. Br J Haematol 2024;204:1856-1861.


Asunto(s)
Hemodilución , Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/patología , Médula Ósea/patología , Estudios Retrospectivos , Examen de la Médula Ósea/métodos , Japón , Células de la Médula Ósea/patología , Células de la Médula Ósea/metabolismo
3.
Br J Haematol ; 203(5): 710-711, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37909166

RESUMEN

In this issue, we publish the last instalment in our series 'Global View' within the 'Wider Perspective' umbrella. In it we query experts from a variety of countries-deliberately trying to encompass both those with strained economies as well as more affluent ones-as to how patients are handled within such widely varying health systems. Commentary on: Hokland et al. AML in the elderly-A global view. Br J Haematol 2023;203:760-773.

5.
Leukemia ; 37(9): 1792-1801, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37464068

RESUMEN

Oncogenic fusion drivers are common in hematological cancers and are thus relevant targets of future CRISPR-Cas9-based treatment strategies. However, breakpoint-location variation in patients pose a challenge to traditional breakpoint-targeting CRISPR-Cas9-mediated disruption strategies. Here we present a new dual intron-targeting CRISPR-Cas9 treatment strategy, for targeting t(8;21) found in 5-10% of de novo acute myeloid leukemia (AML), which efficiently disrupts fusion genes without prior identification of breakpoint location. We show in vitro growth rate and proliferation reduction by 69 and 94% in AML t(8;21) Kasumi-1 cells, following dual intron-targeted disruption of RUNX1-RUNX1T1 compared to a non t(8;21) AML control. Furthermore, mice injected with RUNX1-RUNX1T1-disrupted Kasumi-1 cells had in vivo tumor growth reduction by 69 and 91% compared to controls. Demonstrating the feasibility of RUNX1-RUNX1T1 disruption, these findings were substantiated in isolated primary cells from a patient diagnosed with AML t(8;21). In conclusion, we demonstrate proof-of-principle of a dual intron-targeting CRISPR-Cas9 treatment strategy in AML t(8;21) without need for precise knowledge of the breakpoint location.


Asunto(s)
Leucemia Mieloide Aguda , Translocación Genética , Animales , Ratones , Proteína 1 Compañera de Translocación de RUNX1/genética , Intrones/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Carga Tumoral , Sistemas CRISPR-Cas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Proliferación Celular , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo
6.
Br J Haematol ; 201(2): 199-214, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36799486

RESUMEN

The thalassaemias are a group of genetic disorders of haemoglobin which are endemic in the tropics but are now found worldwide due to migration. Basic standard of care therapy includes regular transfusions to maintain a haemoglobin level of around 10 g/dL, together with iron chelation therapy to prevent iron overload. Novel therapies, bone marrow transplantation, and gene therapy are treatment options that are unavailable in many countries with stressed economies. This Wider Perspectives article presents the strategies for management of an adolescent refugee patient with beta thalassaemia, as it would be performed by expert haematologists in six countries: Italy, Lebanon, Oman, the Sudan, Thailand and the United States. The experienced clinicians in each country have adapted their practice according to the resources available, which vary greatly. Even in the current modern era, providing adequate transfusions and chelation is problematic in many countries. On the other hand, ensuring adherence to therapy, particularly during adolescence, is a similar challenge seen in all countries. The concluding section highlights the disparities in available therapies and puts the role of novel therapies into a societal context.


Asunto(s)
Sobrecarga de Hierro , Talasemia , Talasemia beta , Adolescente , Humanos , Talasemia/epidemiología , Talasemia/terapia , Talasemia beta/epidemiología , Talasemia beta/terapia , Terapia por Quelación , Sobrecarga de Hierro/terapia , Sobrecarga de Hierro/tratamiento farmacológico , Transfusión Sanguínea
8.
Cytometry B Clin Cytom ; 102(2): 107-114, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34648681

RESUMEN

BACKGROUND: Studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown that leukemic blast populations may display immunophenotypic heterogeneity. In the clinical setting, evaluation of measurable residual disease during treatment and follow-up is highly dependent on knowledge of the diversity of blast subsets. Here, we set out to evaluate whether variation in expression of the blast marker, TdT, in T-ALL blasts could correspond to differences in morphometric features. METHODS: We investigated diagnostic bone marrow samples from six individual T-ALL patients run in parallel on imaging flow cytometry (IFC) and conventional flow cytometry (CFC). RESULTS: Guided by the imagery available in IFC, we identified distinct TdTneg and TdTpos subpopulations with apparent differences in internal complexity. As TdTneg blasts predominantly displayed very low forward scatter (FSC) on CFC, these subsets were initially excluded from routine analysis as debris, elements of small diameter, apoptotic, and/or dead cells. However, IFC-based morphometric analyses demonstrated that cell size and shape of TdTneg blasts were comparable to the TdTpos cells and without morphometric apoptotic hallmarks, supporting that the TdTneg subpopulation corresponded to T-ALL blasts. Fluorescence in situ hybridization analyses substantiated the clinical relevance of TdTneg FSCvery-low cells by retrieving known diagnostic cytogenetic abnormalities at comparable frequencies in purified TdTneg FSCvery-low and TdTpos FSCint subsets. CONCLUSION: We highlight this finding as knowledge of phenotypic heterogeneity is of crucial importance in the clinical setting for delineation and quantification of blast subpopulations of potential biological relevance. We argue that the IFC imagery may allow for visual verification and improvement of applied gating strategies.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Enfermedad Aguda , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Linfocitos T
9.
Br J Haematol ; 196(3): 530-547, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34931311

RESUMEN

As haematologists, we always seek to follow standardised guidelines for practice and apply the best treatment within our means for our patients with blood diseases. However, treatment can never follow an exact recipe. Opinions differ as to the best approach; sometimes more than one treatment approach results in identical outcomes, or treatments differ only by the manner in which they fail. Furthermore, the haematologist is faced with constraints relating to the local economic environment. Patients too are not the same the world over. Early presentation is commoner in the developed world, as is the patient's understanding of the disease process. This in turn has an impact on the way patients are managed, the rigorousness of patient adhesion to the treatment schedule and the outcome. Here we take a look at the precursor B-cell acute lymphoblastic leukaemia in an adolescent in a range of different settings from low- to high income countries with widely differing challenges for diagnosis, therpy and follow-up. For these reasons, given the same starting conditions, patients will be treated differently according to the institute and the country they are in. Experts from around the world have been tasked to describe their management plan and rationale for a specific disease presentation. Here they explore the management of precursor B-cell acute lymphoblastic leukaemia (pre-B ALL) in five different institutions worldwide with a focus on those with more or less strained economies. We end with a conclusion from an expert in the field comparing and contrasting these different management styles and considering their merits and limitations.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Testimonio de Experto , Salud Global , Humanos , Estudios Multicéntricos como Asunto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiología
10.
Ugeskr Laeger ; 183(42)2021 10 18.
Artículo en Danés | MEDLINE | ID: mdl-34709164
13.
Acta Haematol ; 144(3): 275-284, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33271547

RESUMEN

INTRODUCTION: In this single-center study of 268 acute myeloid leukemia (AML) patients, we have tested if a subset of 4 routinely employed immunophenotypic stem cell-associated markers correlated with the presence of recurrently mutated genes and if the markers were predictive for mutational status. METHODS: Immunophenotypic data from 268 diagnostic AML samples obtained in 2009-2018 were analyzed retrospectively for the antigens CD34, CD117, CD123, and CLEC12A. Correlation between immunophenotypes and mutations was analyzed by Fischer's exact test. Clinical applicability of the markers for predicting mutational status was evaluated by receiver operating characteristics analyses, where an area under the curve (AUC) of at least 0.85 was accepted as clinically relevant. RESULTS: For a number of genes, the antigen expression differed significantly between mutated and wild-type gene expression. Despite low AUCs, CD123 and CLEC12A correlated with FLT3+NPM1- and FLT3+NPM1+. Three subsets met the AUC requirements (CD34+, CD34+CD117+, and CD34-CD117+) for predicting FLT3-NPM1+ or FLT3+NPM1+. CONCLUSION: The value of immunophenotypes as surrogate markers for mutational status in AML seems limited when employing CD123 and CLEC12A in combination with CD34 and CD117. Defining relevant cutoffs for given markers is challenging and hampered by variation between laboratories and patient groups.


Asunto(s)
Antígenos CD34/metabolismo , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Lectinas Tipo C/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptores Mitogénicos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/genética , Área Bajo la Curva , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunofenotipificación , Subunidad alfa del Receptor de Interleucina-3/genética , Estimación de Kaplan-Meier , Lectinas Tipo C/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Nucleofosmina , Proteínas Proto-Oncogénicas c-kit/genética , Curva ROC , Receptores Mitogénicos/genética , Estudios Retrospectivos , Adulto Joven
14.
Cytometry B Clin Cytom ; 100(5): 554-567, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33285035

RESUMEN

BACKGROUND: The hallmark of myelodysplastic syndrome (MDS) remains dysplasia in the bone marrow (BM). However, diagnosing MDS may be challenging and subject to inter-observer variability. Thus, there is an unmet need for novel objective, standardized and reproducible methods for evaluating dysplasia. Imaging flow cytometry (IFC) offers combined analyses of phenotypic and image-based morphometric parameters, for example, cell size and nuclearity. Hence, we hypothesized IFC to be a useful tool in MDS diagnostics. METHODS: Using a different-from-normal approach, we investigated dyserythropoiesis by quantifying morphometric features in a median of 5953 erythroblasts (range: 489-68,503) from 14 MDS patients, 11 healthy donors, 6 non-MDS controls with increased erythropoiesis, and 6 patients with cytopenia. RESULTS: First, we morphometrically confirmed normal erythroid maturation, as immunophenotypically defined erythroid precursors could be sequenced by significantly decreasing cell-, nuclear- and cytoplasm area. In MDS samples, we demonstrated cell size enlargement and increased fractions of macronormoblasts in late-stage erythroblasts (both p < .0001). Interestingly, cytopenic controls with high-risk mutational patterns displayed highly aberrant cell size morphometrics. Furthermore, assisted by machine learning algorithms, we reliably identified and enumerated true binucleated erythroblasts at a significantly higher frequency in two out of three erythroblast maturation stages in MDS patients compared to normal BM (both p = .0001). CONCLUSION: We demonstrate proof-of-concept results of the applicability of automated IFC-based techniques to study and quantify morphometric changes in dyserythropoietic BM cells. We propose that IFC holds great promise as a powerful and objective tool in the complex setting of MDS diagnostics with the potential for minimizing inter-observer variability.


Asunto(s)
Eritroblastos/patología , Eritropoyesis , Citometría de Flujo , Aprendizaje Automático , Síndromes Mielodisplásicos/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad
15.
J Pers Med ; 10(4)2020 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-33256157

RESUMEN

Measurable residual disease (MRD) response during acute myeloid leukemia (AML) treatment is a gold standard for determining treatment strategy, especially in core-binding factor (CBL) AML. The aim of this study was to critically review the literature on MRD status in the CBF-AML to determine the overall impact of MRD status on clinical outcomes. Published studies in the MEDLINE and EMBASE databases from their inception up to 1 June 2019 were searched. The primary end-point was either overall survival (OS) or recurrence-free survival (RFS) between MRD negative and MRD positive CBF-AML patients. The secondary variable was cumulative incidence of relapse (CIR) between groups. Of the 736 articles, 13 relevant studies were included in this meta-analysis. The MRD negative group displayed more favorable recurrence-free survival (RFS) than those with MRD positivity, with a pooled odds ratio (OR) of 4.5. Moreover, OS was also superior in the MRD negative group, with a pooled OR of 7.88. Corroborating this, the CIR was statistically significantly lower in the MRD negative group, with a pooled OR of 0.06. The most common cutoff MRD level was 1 × 10-3. These results suggest that MRD assessment should be a routine investigation in clinical practice in this AML subset.

16.
Blood Cancer Discov ; 1(1): 48-67, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32974613

RESUMEN

Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that MIR300 has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. MIR300 is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates MIR300 in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating TUG1 long noncoding RNA that uncouples and limits MIR300 function to cytostasis. Genetic and pharmacologic MIR300 modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis in vitro and in patient-derived xenografts; hence, the importance of MIR300 and PP2A activity for CML development and therapy.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , MicroARNs , Humanos , Células Asesinas Naturales , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , MicroARNs/genética , Células Madre Neoplásicas , Inhibidores de Proteínas Quinasas/metabolismo , Proteína Fosfatasa 2/genética , Microambiente Tumoral/genética
19.
Blood Adv ; 4(5): 885-892, 2020 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-32150606

RESUMEN

Therapy-related myeloid neoplasms (tMN) develop after exposure to cytotoxic and radiation therapy, and due to their adverse prognosis, it is of paramount interest to identify patients at high risk. The presence of clonal hematopoiesis has been shown to increase the risk of developing tMN. The value of analyzing hematopoietic stem cells harvested at leukapheresis before autologous stem cell transplantation (ASCT) with next-generation sequencing and immunophenotyping represents potentially informative parameters that have yet to be discovered. We performed a nested case-control study to elucidate the association between clonal hematopoiesis, mobilization potential, and aberrant immunophenotype in leukapheresis products with the development of tMN after ASCT. A total of 36 patients with nonmyeloid disease who were diagnosed with tMN after treatment with ASCT were included as case subjects. Case subjects were identified from a cohort of 1130 patients treated with ASCT and matched with 36 control subjects who did not develop tMN after ASCT. Case subjects were significantly poorer mobilizers of CD34+ cells at leukapheresis (P = .016), indicating that these patients possess inferior bone marrow function. Both clonal hematopoiesis (odds ratio, 5.9; 95% confidence interval, 1.8-19.1; P = .003) and aberrant expression of CD7 (odds ratio, 6.6; 95% confidence interval, 1.6-26.2; P = .004) at the time of ASCT were associated with an increased risk of developing tMN after ASCT. In conclusion, clonal hematopoiesis, present at low variant allele frequencies, and aberrant CD7 expression on stem cells in leukapheresis products from patients with nonmyeloid hematologic cancer hold potential for the early identification of patients at high risk of developing tMN after ASCT.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Neoplasias Primarias Secundarias , Estudios de Casos y Controles , Hematopoyesis Clonal , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Trasplante Autólogo
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